Mutant MMP-9 and HGF Gene Transfer Enhance Resolution of CCl4-Induced Liver Fibrosis in Rats: Role of ASH1 and EZH2 Methyltransferases Repression

被引：54

作者：

Atta, Hussein ^{[1
]}

El-Rehany, Mahmoud ^{[2
]}

Hammam, Olfat ^{[3
]}

Abdel-Ghany, Hend ^{[2
]}

Ramzy, Maggie ^{[2
]}

Roderfeld, Martin ^{[4
]}

Roeb, Elke ^{[4
]}

Al-Hendy, Ayman ^{[5
]}

Raheim, Salama Abdel ^{[2
]}

Allam, Hatem ^{[2
]}

Marey, Heba ^{[2
]}

机构：

[1] Menia Univ, Fac Med, Dept Surg, El Minia, Egypt

[2] Menia Univ, Fac Med, Dept Biochem, El Minia, Egypt

[3] Theodor Bilharz Res Inst, Dept Pathol, Giza, Egypt

[4] Univ Giessen, Dept Gastroenterol, Giessen, Germany

[5] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA

来源：

PLOS ONE | 2014年 / 9卷 / 11期

关键词：

HEPATOCYTE GROWTH-FACTOR; HEPATIC STELLATE CELLS; ACTIVATED RECEPTOR-GAMMA; TISSUE INHIBITOR; MESSENGER-RNA; C-MET; MYOFIBROBLAST TRANSDIFFERENTIATION; INTRAVENOUS-INJECTION; PARTIAL-HEPATECTOMY; IMPROVES SURVIVAL;

D O I：

10.1371/journal.pone.0112384

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Hepatocyte growth factor (HGF) gene transfer inhibits liver fibrosis by regulating aberrant cellular functions, while mutant matrix metalloproteinase-9 (mMMP-9) enhances matrix degradation by neutralizing the elevated tissue inhibitor of metalloproteinase-1 (TIMP-1). It was shown that ASH1 and EZH2 methyltransferases are involved in development of liver fibrosis; however, their role in the resolution phase of liver fibrosis has not been investigated. This study evaluated the role of ASH1 and EZH2 in two mechanistically different therapeutic modalities, HGF and mMMP-9 gene transfer in CCl4 induced rat liver fibrosis. Liver fibrosis was induced in rats with twice a week intraperitoneal injection of CCl4 for 8 weeks. Adenovirus vectors encoding mMMP-9 or HGF genes were injected through tail vein at weeks six and seven and were sacrificed one week after the second injection. A healthy animal group was likewise injected with saline to serve as a negative control. Rats treated with mMMP-9 showed significantly lower fibrosis score, less Sirius red stained collagen area, reduced hydroxyproline and ALT concentration, decreased transforming growth factor beta 1 (TGF-beta 1) mRNA and lower labeling indices of alpha smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) stained cells compared with HGF- or saline-treated rats. Furthermore, TIMP-1 protein expression in mMMP-9 group was markedly reduced compared with all fibrotic groups. ASH1 and EZH2 protein expression was significantly elevated in fibrotic liver and significantly decreased in mMMP-9- and HGF-treated compared to saline-treated fibrotic livers with further reduction in the mMMP-9 group. Conclusion: Gene transfer of mMMP-9 and HGF reduced liver fibrosis in rats. ASH1 and EZH2 methyltransferases are significantly reduced in mMMP-9 and HGF treated rats which underlines the central role of these enzymes during fibrogenesis. Future studies should evaluate the role of selective pharmacologic inhibitors of ASH1 and EZH2 in resolution of liver fibrosis.

引用

页数：11

共 60 条

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